Progress or metastasis of malignant tumors and such diseases as rheumatoid arthritis, diabetic retinopathy, retinopathy of prematurity, senile macular degeneration, neovascular glaucoma, retrolental fibroplasia, neovascular glaucoma, psoriasis, angiofibromas, immune and non-immune inflammation, capillary proliferation within atherosclerotic plaques, hemangiomas, Kaposi's Sarcoma, endometriosis, and hypergeneration of scars after wound healing are now known to be caused by hyperplasia of the blood vessel (particularly the peripheral capillary vessel). As preventive or therapeutic medicines against these diseases and conditions, various neovascularization inhibitors containing angiogenesis-inhibiting substances as active effective ingredients have been developed. The angiogenesis-inhibiting substances reported to date include, for example, medroxyprogesterone (Ashiya, et al: Int. J. Cancer, 1989, 44, 895), sulfated protamine (Ogawa et al: Exp. Pathol., 1986, 30, 143), combination of heparin and cortisone (J. Folkman, et al: Science, 1983, 221, 719), prednisolone acetate (J. B. Robin: Arch. Opthalmol., 19855, 103, 284), herbimycin A (Japanese Patent Provisional Publication No. 295, 509/88), peptide from retinal pigment epithelial cell (U.S. Pat. No. 4,996,159), sulfated polysaccharide (U.S. Pat. No. 4,900,815), and phenol derivatives (EP-A-295,037). These angiogenesis-inhibiting substances are not, however, completely satisfactory as preventive or therapeutic medicaments against the above-mentioned diseases and conditions because of the insufficient inhibitory effect of angiogenesis in some cases.
There has been much scientific interest in the search for new inhibitors of angiogenesis because of the hope that this inhibition of new blood vessels would limit the growth of neoplastic tumors which depend on new vascular growth. As a normal cell develops into a solid tumor it undergoes a series of changes. At the physiological level, growth is enhanced, immunity evaded, and neovascularization induced. Neovascularization or angiogenesis appears to be a prerequisite. Experimental solid tumors are unable to grow beyond a few millimeters in thickness without a blood supply. Most natural solid tumors elaborate angiogenic factors that attract the new vessels on which they depend. It has become increasingly evident that once a solid tumor has been established in the body, every increase in tumor cell population must be preceded by an increase in new capillaries that converge upon the tumor. Consequently, there has been a continuing research effort directed toward the question of what prevents rampant capillary proliferation and what maintains the quiescent state of the capillary endothelial cells of normal tissues. There has also been an active search for a therapeutic agent or agents which can cause capillary regression. Identification of such an agent has proven to be a very difficult problem. About the only demonstrable difference between tumor angiogenesis and other types of non-neoplastic angiogenesis is a greater intensity and persistence of the angiogenesis induced by tumors.
There is a generally recognized lack of a therapeutic agent which can effectively inhibit tumor neovascularization and limit or even completely stop the growth of tumors.